The histamine H3 receptors are found in the central and peripheral nervous systems. The administration of histamine H3 receptor ligands may influence the histamine levels or the secretion of neurotransmitters in the brain and the periphery and thus can be useful in the treatment of several disorders, including Alzheimer's disease and other dementias, obesity, central nervous system disorders such as vigilance and sleep disorders, narcolepsy, Parkinson's disease, attention-deficit hyperactivity disorder, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive disorders, depression, anxiety, cardiovascular disorders, and gastrointestinal disorders.
To illustrate, a number of studies in the literature have demonstrated the cognitive enhancing properties of histamine H3 receptors antagonists in rodent models (See, e.g., Giovannini et al., Behav. Brain Res., 104, 147-155 (1999)). These reports further suggest that antagonists and/or inverse agonists could be useful for the treatment of cognitive impairments in neurological diseases such as Alzheimer's disease and related neurodegenerative disorders. Alzheimer's disease is the most common cause of dementia in the elderly, and is often characterized with one or more symptoms such as memory loss, confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, withdrawal of the sufferer, and loss of motor control.
2-(Cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide, which has the structure of Formula (I):
is a potent histamine H3 receptor antagonist with inverse agonist properties. The preparation, physical properties and beneficial pharmacological properties of 2-(cyclohexyl methyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide are described in, for example, WO2005/118547 (also US2007/0105834). In WO2005/118547, 2-(cyclohexyl methyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is described as being in the free base form, which is a viscous oil, or in the form of an oxalate salt, which has low crystallinity and thermal stability.
Although it is known that the preparation of salt forms may improve the physical or pharmaceutical properties of a pharmaceutically active compound, it is not possible to predict which salt forms may possess advantages for a particular purpose prior to the actual preparation and characterization of the salt form. In particular, such advantages, in a non-limiting manner could include, physical forms of the salt in that it provides better processability, solubility or shelf life stability, just to name a few. Other advantages may also include biological properties such as improved bioavailability, reduced adverse reactions at the GI tract (for example irritation of the GI tract, partial degradation of the compound, etc.), or better deliverability of the drug to the intended target site among other advantages.
The present invention therefore provides fumarate salts of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide which exhibit advantageous properties which differentiate the fumarate salts from the base form of 2-(cyclohexyl methyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide itself, and over other salt forms of 2-(cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide known in the art.
Furthermore, the crystallinity and stability profile of the difumarate monohydrate salt of 2-(cyclohexyl methyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide make this solid form unpredictably and particularly useful as a medicament.